Pancreatic cancer (PDAC) is the 4th leading cause of cancer-related death in the U.S. and other industrialized countries [1]. Despite massive efforts, it remains a devastating disease, its 5 year survival rate is less than 5% and average median survival is less than 1 year [1]. This grim prognosis is mostly due to its often late initial diagnosis at an incurable advanced stage, frequently after metastasis.
PDAC is believed to progress through precursor lesions termed pancreatic intraepithelial neoplasia (PanIN) to invasive cancer, similar to the adenoma-carcinoma sequence observed in other malignancies. Lesions progress from adenoma (PanIN I) to adenoma with dysplasia (PanIN II), to carcinoma in situ (PanIN III) and finally invasive cancer [2, 3, 4]. Despite this well characterized carcinogenesis through precursor lesions, effective early detection and screening for PDAC are still unavailable. This is mostly due to the absence of diagnostic tools and biomarkers for early cancer. Ideally, a biomarker for PDAC should therefore not only detect invasive cancer, but also its precursor lesions, PanIN II and more importantly pre-invasive malignant PanIN III lesions. Currently, CA 19.9 is the only clinically used serum biomarker for PDAC. However, it lacks specificity and sensitivity, especially for the detection of small cancers and the differentiation of malignant and benign pancreatic disease [5]. CA 19.9 is therefore unsuitable for screening or early detection of PDAC. Invasive endoscopic procedures (EUS and ERCP) can detect some early lesions, but suffer from potential for injury to the pancreas, high false negative rates and are highly operator dependent [6, 7]. They also often fail to distinguish malignant from benign or premalignant lesions [8, 9]. Cross-sectional abdominal imaging has also proven unreliable for the detection of early stage PDAC, especially in high-risk patients [10, 11]. It fails to detect metastases in up to 30% of patients with PDAC preoperatively [12, 13] and does not safely differentiate between chronic pancreatitis (CP) and PDAC [14, 15]. The reliable distinction of PDAC and chronic pancreatitis is important, but often difficult to make. Both diseases share many clinical signs and symptoms, but profoundly different treatment strategies are employed for each. While the only available curative treatment for PDAC is radical surgical resection, the treatment of chronic pancreatitis is focused on symptomatic improvement, which most often can be achieved without surgery [14, 15].
Novel biomarkers and non-invasive imaging strategies that overcome the shortcomings of currently employed diagnostic tools, would allow a reliable distinction of PDAC and chronic pancreatitis. They would also permit the earlier diagnosis and consequently treatment of PDAC before the onset of metastasis. They are therefore much needed and may ultimately aid in improving survival [16]. Recently, Plectin-1 (Plec1) was suggested to be a potential novel imaging biomarker for PDAC based on findings in vitro and in a genetically engineered mouse model [17]. Peptide ligands were identified for use in detecting Plec1 [17]. However, the suitability of Plec1 as a biomarker for human PDAC and its precursor lesions remains to be assessed. Plec1 has been identified as a biomarker for malignant pancreatic “intraductal papillary mucinous neoplasms” (IPMN) and has been hypothesized to be a marker for the early detection of carcinoma arising in IPMN (Bausch et al., 2009, J. Gastrointest. Surg., 13:1948), as a biomarker for non-small cell lung cancer (Harris, 2009, J. Clin. Oncology, 27, No. 15S (May 20 Supplement): e22118), and for human colorectal adenoma and adenocarcinoma (Lee, 2004, J. Med., 35:(1-6):141-149). One peptide ligand for Plec1 is the peptide KTLLPTP (SEQ ID NO:1) [Kelly et al. (2008) Targeted nanoparticles for imaging incipient pancreatic ductal adenocarcinoma. PLoS Med 5:4:e85; International Pat. Pub. No. WO 2009/129220, Kelly et al., published Oct. 22, 2009].
There is a long felt need in the art for better cancer biomarkers, for new and better reagents which recognize biomarkers, to aid in diagnosing, monitoring, and localizing cancers. The present invention satisfies these needs.